What is the incidence of interaction of SSRIs with methylene blue? What would be the alternative to methylene blue if a provider wanted to examine for a leak?

Comment by InpharmD Researcher

As a diagnosis of exclusion, the prevalence of serotonin syndrome is difficult to quantify due to the high index of suspicion needed by the physician. Some epidemiological data suggest an incidence rate of 14%-16% when overdosing on an SSRI and an 0.6-2.3 case per 10,000 years when triptans are co-administrated with SSRI. Other analyses suggest the incidence of confusion or neuropsychiatric symptoms among patients taking SRIs who received methylene blue to be as high as 38043%. However, patients were frequently on concomitant regimens that can exacerbate their risk of developing serotonin syndrome, and data are primarily derived from case reports. While there are insufficient data to suggest a prevalence rate for methylene blue for serotonin syndrome, the majority of reported cases involved concomitant use of serotonin receptor inhibiting agents. Alternatives to use of methylene blue may be other dyes (e.g., fluoresceine, indocyanine green), as well as high-resolution ultrasound or radionuclide scanning.

Background

The increasing incidence rates of serotonin syndrome are believed to parallel the increased frequency of selective serotonin reuptake inhibitor (SSRI)/selective norepinephrine reuptake inhibitor (SNRI) use. Symptoms of serotonin syndrome may also be confused with other central nervous system pathologies or overlooked entirely, as recognition of serotonin syndrome is more a diagnosis of exclusion and requires a high index of suspicion. Combination with other drugs (e.g., monoamine oxidase inhibitors [MAOIs], tricyclic antidepressants, cough medicine, etc.) may also potentiate the risk of developing serotonin syndrome. Because of these factors, measuring the incidence rate of serotonin syndrome caused by SSRI/SNRI and methylene blue is deemed a difficult endeavor. [1], [2]

Methylene blue can precipitate severe serotonin toxicity when administered to patients taking SSRIs due to its mechanisms as a potent reversible inhibitor of monoamine oxidase A (MAO-A), the enzyme responsible for serotonin metabolism. SSRIs increase extracellular serotonin by blocking serotonin reuptake, while methylene blue inhibits serotonin breakdown; together, this combination can substantially increase serotonergic activity and produce a serotonin-toxicity toxidrome characterized by agitation, confusion, hyperreflexia, clonus, tremor or jerky movements, hypertension, and hyperthermia. The interaction appears particularly relevant in perioperative settings, such as parathyroid surgery where methylene blue has been used for gland localization, because postoperative neurologic changes may be misattributed to delirium or metabolic encephalopathy. Additional reports and retrospective series elucidate that among 325 parathyroidectomy patients given methylene blue, CNS toxicity occurred in 17 of 45 patients taking SSRIs preoperatively, compared with no cases among 280 patients not taking SSRIs. Even common methylene blue doses used clinically may exceed concentrations required for MAO-A inhibition. [3]

A 2010 systematic review examined whether methylene blue can precipitate serotonin syndrome when given to patients receiving serotonin reuptake inhibitors or other highly serotonergic antidepressants. Although historically considered relatively safe, the review focused on a series of postoperative neurologic and autonomic complications occurring after intravenous methylene blue, especially in patients taking SSRIs or SNRIs. The authors searched MEDLINE and PsychInfo through September 2008 and included studies in which patients received methylene blue and then developed acute confusional states, neuropsychiatric complications, or autonomic instability. A total of 9 case reports and 2 retrospective reviews were identified. In total, 26 patients developed postoperative confusion or neuropsychiatric symptoms after intravenous methylene blue; 24 were taking a serotonin reuptake inhibitor and 1 was taking clomipramine, a tricyclic antidepressant with strong serotonergic activity. [4]

The case reports primarily involved patients undergoing elective parathyroidectomy with methylene blue used for gland localization, although one patient received methylene blue for persistent hypotension during mitral valve replacement. Most affected patients were taking SSRIs or SNRIs such as fluoxetine, paroxetine, venlafaxine, citalopram, or clomipramine, and their antidepressants were generally continued until the day of surgery. Reported methylene blue doses ranged from lower doses such as 1.75 to 2 mg/kg to standard parathyroidectomy doses of 5 to 7.5 mg/kg. Clinical manifestations varied but commonly included confusion, agitation, reduced consciousness, aphasia, hyperthermia, diaphoresis, hypertonicity, tremor, hyperreflexia, myoclonus, nystagmus, and abnormal limb movements consistent with possible clonus. Several patients required ICU admission, reintubation, or prolonged ventilator support; one patient had a prolonged hospitalization, required hemodialysis, and recovered over approximately 2 weeks. Despite the severity of symptoms, all 9 case-report patients recovered with supportive care. [4]

Additionally, two retrospective parathyroidectomy audits provided the strongest incidence signal. In one review of 193 parathyroidectomies using methylene blue 7.5 mg/kg, 12 patients developed toxic metabolic encephalopathy characterized mainly by confusion and difficulty arousing; all 12 were taking serotonin reuptake inhibitors. Among patients taking SRIs, the incidence of postoperative encephalopathy was 43%. In a second review of 132 parathyroidectomies using methylene blue doses of 3 to 5 mg/kg, 5 patients taking SRIs developed postoperative encephalopathy with confusion, lethargy, and aphasia; 2 required reintubation, and symptom onset occurred within 1 to 5 hours. Among patients taking SRIs in this study, the incidence of neurologic complications was 29%. When pooled, the retrospective data showed an overall 38% incidence of confusion or neuropsychiatric symptoms among patients taking SRIs who received methylene blue, with mean symptom duration of 42.1 hours and a range from 1 hour to 2 weeks. [4]

Overall, the review concluded that intravenous methylene blue can cause a serious adverse reaction consistent with serotonin syndrome when given to patients taking SRIs or other highly serotonergic antidepressants. The authors recommended that psychiatrists, surgeons, anesthesiologists, and critical-care clinicians recognize this interaction before planned procedures or urgent use of methylene blue. For elective parathyroid surgery, they suggested considering alternative localization strategies, such as high-resolution ultrasound or radionuclide scanning, when antidepressants cannot be safely discontinued. They also noted that simply stopping antidepressants before surgery may not always be practical or safe, particularly because some SRIs have long half-lives and discontinuation may destabilize psychiatric illness. For vasodilatory shock or other urgent indications, the authors advised extreme caution if methylene blue is used in patients taking serotonergic drugs. [4]

A 2023 meta-analysis compared indocyanine green (IG) fluorescence versus blue dye, technetium-99m, or both in sentinel lymph node (SLN) detection in early breast cancer patients. However, from a total of 39 included studies, the results largely favor IG. The consistency of superiority analysis, where SLN detection metrics were 2.00 to 4.99% or ≥ 5.00% greater for IG than blue dye/99mTc, suggests that IG was superior to blue dye 73 times versus 1, to technetium-99m 42 times versus 9, and to technetium-99 plus blue dye 6 times versus 0. Therefore, utilizing alternatives to IG for early breast cancer screening may not be appropriate. [5]

Background References: [1] Volpi-Abadie J, Kaye AM, Kaye AD. Serotonin syndrome. Ochsner J. 2013;13(4):533-540.
[2] Boyer EW, Shannon M. The serotonin syndrome [published correction appears in N Engl J Med. 2007 Jun 7;356(23):2437] [published correction appears in N Engl J Med. 2009 Oct 22;361(17):1714]. N Engl J Med. 2005;352(11):1112-1120. doi:10.1056/NEJMra041867
[3] Stanford SC, Stanford BJ, Gillman PK. Risk of severe serotonin toxicity following co-administration of methylene blue and serotonin reuptake inhibitors: an update on a case report of post-operative delirium. J Psychopharmacol. 2010;24(10):1433-1438. doi:10.1177/0269881109105450
[4] Ng BK, Cameron AJ. The role of methylene blue in serotonin syndrome: a systematic review. Psychosomatics. 2010;51(3):194-200. doi:10.1176/appi.psy.51.3.194
[5] White KP, Sinagra D, Dip F, et al. Indocyanine green fluorescence versus blue dye, technetium-99M, and the dual-marker combination of technetium-99M + blue dye for sentinel lymph node detection in early breast cancer-meta-analysis including consistency analysis. Surgery. 2024;175(4):963-973. doi:10.1016/j.surg.2023.10.021
Literature Review

A search of the published medical literature revealed 3 studies investigating the researchable question:

What is the incidence of interaction of SSRIs with methylene blue? What would be the alternative to methylene blue if a provider wanted to examine for a leak?

Level of evidence

C - Multiple studies with limitations or conflicting results  Read more→


Please see Tables 1-3 for your response.

 

Risk of severe serotonin toxicity following co-administration of methylene blue and serotonin reuptake inhibitors: an update on a case report of post-operative delirium

Design

 Case report

Case presentation

The case involved a patient who developed postoperative delirium after parathyroidectomy while having recently taken paroxetine. In the original report, the event was suspected to represent serotonin toxicity, but the cause was unclear because paroxetine had been stopped 2 days before surgery and methylene blue was not initially recognized as a relevant drug exposure. On reassessment, the authors confirmed that methylene blue had been administered approximately 2 hours before surgery for parathyroid gland visualization. The patient developed agitation, confusion, uncontrolled limb movements, dilated pupils, brisk reflexes, ankle clonus, hypertension, and hyperthermia, which the authors considered highly consistent with serotonin toxicity.  

Study Author Conclusions

 Rsidual paroxetine, despite a 2-day washout, likely interacted with methylene blue’s MAO-inhibiting activity to produce severe serotonin toxicity. The paper also notes that paroxetine’s usual half-life is about 24 hours, and in some patients may be substantially longer, meaning clinically relevant residual SSRI exposure may persist after brief discontinuation.
Table 1 References:
[6] Stanford SC, Stanford BJ, Gillman PK. Risk of severe serotonin toxicity following co-administration of methylene blue and serotonin reuptake inhibitors: an update on a case report of post-operative delirium. J Psychopharmacol. 2010;24(10):1433-1438. doi:10.1177/0269881109105450

 Life-Threatening Serotonin Syndrome Due to Methylene Blue-Citalopram Interaction

Design

 Case report

Case presentation

A 49-year-old patient presented to the emergency department after being found obtunded on a park bench surrounded by pill bottles, including an empty hydralazine bottle and a half-empty carvedilol bottle. His history included hypertension, sciatica, anxiety disorder, major depressive disorder treated with citalopram, prior suicide attempts, and polysubstance use. On arrival, he was hypotensive at 65/28 mm Hg, somnolent with a Glasgow Coma Scale score of 4, and required endotracheal intubation for airway protection. He was admitted to the medical ICU for management of suspected carvedilol and hydralazine overdose. Despite IV fluids and maximal doses of two vasopressors, he remained hypotensive, so glucagon, IV lipid emulsion, and methylene blue were started, with methylene blue given as a 1 mg/kg bolus followed by 0.5 mg/kg/hour infusion. His hemodynamics initially improved, but 16 hours later he developed severe hyperthermia to 109°F, diffuse muscular rigidity, hyperreflexia, elevated creatine phosphokinase, and acute kidney injury. Serotonin syndrome was suspected due to interaction between methylene blue and citalopram. Methylene blue was discontinued, and he was treated with dantrolene, cyproheptadine, external cooling, IV fluids, and urine alkalinization. Over a 15-day hospitalization, vasopressors were tapered, he was extubated, creatine kinase and creatinine normalized, and he was discharged to a rehabilitation facility with social work and psychiatry follow-up. 

Study Author Conclusions

 Mthylene blue, while useful for refractory hypotension through nitric oxide synthase and guanylate cyclase inhibition, is also a strong monoamine oxidase inhibitor and may precipitate life-threatening serotonin syndrome when used with SSRIs such as citalopram.
Table 2 References:
[7] Hashmi AT, Gupta SS, Shankar S, Seneviratne C, Yoon TS, Kupfer Y. Life-Threatening Serotonin Syndrome Due to Methylene Blue-Citalopram Interaction. Am J Ther. 2019;26(6):e740-e741. doi:10.1097/MJT.0000000000000897

 

Serotonin Syndrome After Methylene Blue Administration During Cardiac Surgery: A Case Report and Review

Design

 Case report

Case presentation

A 64-year-old patient presented for mitral valve repair for severe mitral regurgitation. Her history included depression treated with paroxetine, as well as use of quetiapine and clonazepam; other medical history included autoimmune hepatitis, stable multiple sclerosis, prior wedge excision of the left upper lung lobe for adenocarcinoma, and a significant smoking history. The surgical course was largely unremarkable, but after initiation of cardiopulmonary bypass she developed persistent hypotension that did not respond adequately to norepinephrine infusion and intermittent boluses. Suspected vasoplegia was treated with vasopressin and methylene blue 2 mg/kg. She was extubated in the operating room, but on postoperative ICU admission she was somnolent, responsive only to verbal stimuli, and noted to have mydriasis. Over the next 8 hours, her neurologic status worsened, with fever to 40.5°C, hypertonic extremities, and nystagmus. Laboratory abnormalities included hyperkalemia, acute kidney dysfunction, and elevated creatine kinase. Brain CT ruled out intracranial hemorrhage and ischemic stroke. Because she had received methylene blue in the setting of serotonergic medications, serotonin syndrome was suspected; paroxetine and quetiapine were stopped. Malignant hyperthermia was considered less likely because symptoms developed gradually and improved with sedation. She was treated supportively with midazolam sedation, reintubation, IV fluids, passive cooling, and discontinuation of suspected causative agents. Her temperature normalized within 6 hours, kidney function improved within 3 days, and liver enzymes and creatine kinase normalized within 4 days. She was successfully weaned from sedation and ventilation by postoperative day 3, transferred to the ward on postoperative day 7, and discharged to another hospital on postoperative day 12 after complete recovery.

Study Author Conclusions

 Mthylene blue can be useful for catecholamine-refractory vasoplegia after cardiopulmonary bypass, but because it inhibits monoamine oxidase A, it may precipitate serotonin syndrome when administered to patients receiving serotonergic psychiatric medications such as SSRIs.
Table 3 References:
[8] Wolvetang T, Janse R, Ter Horst M. Serotonin Syndrome After Methylene Blue Administration During Cardiac Surgery: A Case Report and Review. J Cardiothorac Vasc Anesth. 2016;30(4):1042-1045. doi:10.1053/j.jvca.2015.11.019